Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family

TLDR

A brief postnatal window exists during which the mammalian heart can regenerate after ventricular apex amputation. The study aims to determine whether neonatal mice can regenerate after myocardial ischemia, the leading cause of human heart failure. The authors induced ischemic myocardial infarction in 1‑day‑old mice, producing extensive necrosis and systolic dysfunction. The neonatal heart regenerated fully within 21 days through proliferation of preexisting cardiomyocytes, and miR‑15 family inhibition in early postnatal life boosts adult cardiomyocyte proliferation and improves ventricular function after MI, showing miR‑15 drives loss of regenerative capacity.

Abstract

We recently identified a brief time period during postnatal development when the mammalian heart retains significant regenerative potential after amputation of the ventricular apex. However, one major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-d-old mice and found that this results in extensive myocardial necrosis and systolic dysfunction. Remarkably, the neonatal heart The neonatal heart mounted a robust regenerative response, through proliferation of preexisting cardiomyocytes, resulting in full functional recovery within 21 d. Moreover, we show that the miR-15 family of microRNAs modulates neonatal heart regeneration through inhibition of postnatal cardiomyocyte proliferation. Finally, we demonstrate that inhibition of the miR-15 family from an early postnatal age until adulthood increases myocyte proliferation in the adult heart and improves left ventricular systolic function after adult MI. We conclude that the neonatal mammalian heart can regenerate after myocardial infarction through proliferation of preexisting cardiomyocytes and that the miR-15 family contributes to postnatal loss of cardiac regenerative capacity.